ABSTRACT Purpose: A single-site, randomized, blinded, prospective clinical trial is proposed to determine the significance of a combined isokinetic strength and aerobic exercise training program on the rehabilitation of peripheral nerve function in type 2 diabetic veterans with neuropathy. Background and Significance: Obesity is a major factor in the increasing rates of diabetes and its related complications. Diabetes affects greater than 7% of the population. Veterans are at even greater risk, with approximately 16% currently receiving treatment at Department of Veterans Affairs Medical Centers for diabetes. More than half of affected veterans experience debilitating complications of diabetes, including peripheral neuropathy (PN). Exercise training, in combination with pharmacologic intervention, is now recognized as a cornerstone of management for diabetes. Therapeutic interventions currently available for the treatment of PN in diabetic patients are limited, however, to pain management and stringent glycemic control. Exercise is reported to significantly decrease peripheral nerve microvascular complications common among chronic diabetics. Our preliminary findings demonstrate that exercise intervention improves peripheral nerve function in the diabetic veteran with PN. Intervention strategies, such as proposed in this application, offer a unique and novel therapeutic option for the rehabilitation of the neuro-compromised diabetic veteran. Methods &Research Plan: One-hundred subjects will be recruited for this 24-week study. Subjects each will be randomly assigned to aerobic, isokinetic strength training, combined aerobic and strength training, or non-exercise (control) intervention groups. Isokinetic strength training (Biodex System 3), aerobic exercise training (treadmill), or the combination of strength and aerobic training will be administered 3x per week for the initial 12 weeks. Control subjects will receive 12 clinical visits over the course of the initial 12 weeks. The effects of exercise training type, compared with control subjects, on recovery of peripheral nerve function will be rigorously determined from baseline, 12- and 24-week testing using electrodiagnostic primary outcome measures, Quantitative Sensory Testing, and a battery of validated qualitative and quantitative secondary outcome measures that include an incremental symptom-limited treadmill test, peak torque, Total Neuropathy Score, visual analogue pain scale, and quality of life SF-36V Health Survey. Sustainability of effect will be determined at 24-weeks.The individual effects of exercise training type, compared with control subjects, on tissue oxygenation will be determined from baseline, 12- and 24-week testing by non-invasive quantitated infrared spectroscopy using an InSpectraTM Tissue Spectrometer. Expected Outcomes: This study will objectively and critically determine the type and combination of exercise needed to rehabilitate the neuro-compromised diabetic Veteran. Guided exercise protocols may prove to be practical therapeutic options for the prophylactic management of diabetic subjects with neuropathy. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: RELEVANCE TO PUBLIC HEALTH. HEALTH CARE SIGNIFICANCE OF PROBLEM: Diabetes mellitus afflicts more than 20 million Americans and is the main cause of kidney failure, new onset blindness, and neuropathy-associated limb amputations in adults.(7) Type 2 diabetes accounts for up to 95% of all diabetic cases and affects 7% of the U.S. population age 20 and older. Type 2 diabetes and its associated complications is strongly associated with obesity, secondary to physical inactivity and over-nutrition. The prevalence of type 2 diabetes has conservatively tripled in the last 30 years. Individuals with a body mass index (BMI) of 30 or more have a 5-fold greater risk of diabetes compared to subjects with BMI of 25 or less. In a major clinical trial conducted by the Diabetes Prevention Program (DPP), exercise reduced the risk of getting type 2 diabetes by 58%.(12) It is well established that exercise is a safe and integral approach to the management of patients with diabetes.(10-12) However, the management of neuropathy in type 2 diabetic patients remains palliative. Exercise significantly decreases peripheral nerve microvascular complications in the diabetic patient.(13) Therapeutic interventions that improve blood flow to peripheral nerves, such as exercise, are expected to slow or perhaps reverse the progression of neuropathy in the diabetic patient.(14) In a one-year study of lifestyle (diet and exercise) intervention, Smith et al.(34) observed a modest improvement in intraepidermal nerve fiber density with decreased neuropathic pain and improved sural sensory responses. Recently, we reported improved measures of peripheral nerve function in diabetic patients following a 24-week program of moderate aerobic exercise.(15) Muscle strength in symptomatic diabetic neuropathic patients, however, is markedly reduced when compared to control subjects and non-neuropathic diabetic patients.(56) This may represent a ceiling to the effectiveness of aerobic exercise one may observe among diabetic subjects. To address this concern, we considered different forms of exercise, such as isokinetic in comparison to isotonic, as a way to maximize the amount of muscle activation per unit of work.(57) While there are no published data demonstrating effectiveness of isokinetic training on recovery of peripheral nerve function in diabetic subjects, we argue that an exercise program utilizing strength and aerobic training, as proposed in this application, is strongly anticipated to produce measurable and meaningful therapeutic benefits to the diabetic veteran with neuropathy. RELEVANCE TO VETERAN HEALTH: Approximately 16% of U.S. Veterans are treated for diabetes.(1) At least 8-10% of the treated VA population now suffers with diabetic neuropathy. For these patients, improved treatment is expected to produce an improved quality of life, a decrease in the disabling burden of diabetic nerve dysfunction, and a diminished need for medical care. Although specific costs for treating diabetic neuropathies are not available, the potential savings with better management of diabetic neuropathies is evident given the large number of such patients cared for by the VA. With an aging Veteran population, the number of diabetic neuropathic patients in need of VA medical services is expected to increase considerably.